PROJECT SUMMARY Late-onset Alzheimer?s disease (LOAD) is a genetically complex and thought to be influenced, at least in part, across a number of different loci. Genome-wide association studies (GWAS) have helped fill in the missing gaps, by uncovering several novel genes for LOAD. EPHA1, encoding for the EphA1 receptor, a member of the erythropoietin-producing hepatocellular (Eph) family of receptor tyrosine kinases was identified as a potential locus in a GWAS and subsequently causal mutations were found by us. Physiologically, the Eph receptor family regulates various developmental processes, especially in the CNS, controlling neuron maturation, axon guidance and synapse formation. Aberrant signaling by two members, EphA4 and EphB2, has been directly implicated in A?-mediated synaptic dysfunction and behavioral impairment. As for EphA1, the precise molecular nature of its involvement in AD remains uncertain. We find (preliminary data) that EphA1 levels may be upregulated in LOAD brain, suggesting that increased signaling may underlie one or more AD-associated changes. The mutation (P460L) we reported is a rare gain-of-function coding mutation for EphA1 supporting that conclusion. Together these results suggest a role for chronic activation of EphA1 in LOAD. This means that, of the 14 receptors in the Eph family, 3 have been associated with LOAD, either molecularly or genetically, hinting at a much larger and global role for Eph signaling in LOAD pathogenesis. The overall objective of this proposal is to understand the impact of altered function in specific Eph related genes and the related pathway, in particular variant-specific associations, expression and effect on LOAD pathogenesis. Given the importance of Eph genes in normal cell function, we hypothesize that coding mutations altering protein function, such as EphA1-P460L, will impact one or more downstream pathways involved in LOAD. Ultimately, understanding the function of the Eph-pathway may provide insight into the treatment of LOAD. We will harmonize existing next generation sequence datasets on multiplex Caribbean Hispanic, Caucasian and African American families and a multi-ethnic case-control set and test the association of Eph receptors with risk of LOAD. Subsequently, we will characterize the molecular mechanism(s) involved in altered function of identified Eph variants starting with EphA1-P460L how this contributes to LOAD pathogenesis.